This invention relates to compounds that inhibit p38 MAP kinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Arend, W. P. Arthritis and Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin""s disease (see., Benharroch, D.; et. al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer""s disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Maini, R. N.; et. al. APMIS. 105(4): 257-263, (1997); Feldmann, M., J. of the Royal College of Physicians of London 30(6): 560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology 156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al. Clin. and Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. and Exp. Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., Cooper, A. L., et. al. Am. J. of Physiology 267(6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al. J. of Neuroimmunol. 72(2): 163-168, (1997)) and periodontal diseases.
Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammatory cytokines is considered one of the most effective strategies to block chronic inflammation and have positive therapeutic outcomes.
It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((see., Lee, J. C., et al. Nature 372 (6508): 739-46, (1994)). Compounds that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.
It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I): 
wherein:
R1 is heteroaryl;
 represents a bond between either B and CR1 or Q and CR1 such that:
(i) when  is between Q and xe2x80x94CR1xe2x80x94 then:
B is nitrogen;
R2 is aryl; and
Q is xe2x80x94CRxe2x80x94 wherein:
R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, xe2x80x94OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), xe2x80x94COOR7 (where R7 is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 independently represent hydrogen, alkyl or heteroalkyl); and
(ii) when  is between B and xe2x80x94CR1xe2x80x94 then:
B is carbon;
R2 is aryl or heteroaryl; and
Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 wherein:
R4 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, xe2x80x94OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), xe2x80x94SO2Rxe2x80x3 (where Rxe2x80x3 is alkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 independently represent hydrogen, alkyl or heteroalkyl), -(alkylene)-Z or -(alkyl)-CO-(alkylene)-Z wherein:
Z is cyano;
xe2x80x94COOR7 where R7 is hydrogen or alkyl;
xe2x80x94CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or -(alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle;
xe2x80x94C(xe2x95x90NR10)(NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl, or R10 and R11 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3 and R12 is hydrogen or alkyl; or
xe2x80x94COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and 
is a group represented by formula (S), (T), (U), (V) or (W); 
where:
R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, xe2x80x94COOR14, -(alkyl)-COOR14 (where R14 is hydrogen or alkyl), xe2x80x94CONR15R16 (where R15 and R16 independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attached form a heterocycle), xe2x80x94S(O)nR17 (where n is an integer from 0 to 2 and R17 is alkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94OR18 (where R18 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), xe2x80x94NRC(O)Rxe2x80x3 [where R is hydrogen, alkyl or hydroxyalkyl and Rxe2x80x3 is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or
xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl an Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)]; and R3 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, xe2x80x94OR19 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), xe2x80x94COOR20 (where R20 is hydrogen or alkyl), xe2x80x94CONR21R22 (where R21 and R22 independently represent hydrogen, alkyl or heteroalkyl, or R21 and R22 together with the nitrogen atom to which they are attached form a heterocycle),
xe2x80x94S(O)nR23 (where n is an integer from 0 to 2 and R23 is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), -(alkylene)-Zxe2x80x3 or -(alkyl)-CO-(alkylene)-Zxe2x80x3 wherein:
Zxe2x80x3 is cyano;
xe2x80x94COOR24 where R24 is hydrogen or alkyl;
xe2x80x94CONR25R26 where R25 and R26 independently represent hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycle;
xe2x80x94C(xe2x95x90NR27)(NR28R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3 and R29 is hydrogen or alkyl; or
xe2x80x94COR30 where R30 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and
their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R3 and R6 are not either amino, monosubstituted amino or disubstituted amino.
In a second aspect, this invention provides compounds selected from the group of compounds represented by Formula (IIa): 
wherein:
One of Z1 and Z2 is nitrogen and the other is xe2x80x94CR6xe2x80x94 wherein R6 is hydrogen, alkyl, or alkoxy; or both Z1 and Z2 are nitrogen such that:
(a) when Z1 or Z2 is nitrogen and the other is xe2x80x94CR6xe2x80x94 then:
(i) when Y is halo, then xe2x80x94Qxe2x80x94R is xe2x80x94NHxe2x80x94C(R1)xe2x95x90CH(R2) or xe2x80x94Nxe2x95x90C(CH3)(R1);
(ii) when Y is xe2x80x94C(R2)xe2x95x90C(R1)OX (where X is p-CH3C6H4SO2xe2x80x94, CH3SO2xe2x80x94, or CF3SO2xe2x80x94), then xe2x80x94Qxe2x80x94R is nitro or amino; and
(iii) when Y is xe2x80x94C(O)R2, then xe2x80x94Qxe2x80x94R is xe2x80x94NHC(O)R1, xe2x80x94OCH2CO2R, or xe2x80x94SCH2R1 where:
R is alkyl;
R1 is heteroaryl; and
R2 is aryl or heteroaryl; and
(b) when Z1 and Z2 both are nitrogen then:
Y is halo and xe2x80x94Qxe2x80x94R is xe2x80x94NHxe2x80x94C(R1)xe2x95x90CH(R2) where R1 and R2 are as defined above; and
R3 is hydrogen, alkyl, halo, or alkoxy.
In a third aspect, this invention provides compounds selected from the group of compounds represented by Formula (IIb): 
wherein:
Z3 is nitrogen and Z4is xe2x80x94CR3xe2x80x94 wherein R3 is hydrogen, alkyl, or alkoxy; or Z4 is nitrogen and Z3 is xe2x80x94CHxe2x80x94; such that:
(a) when Y is hydrogen, then xe2x80x94Qxe2x80x94R is xe2x80x94NHxe2x80x94Nxe2x95x90C(R1)CH2(R2); and
(b) when Y is xe2x80x94C(O)R2, then xe2x80x94Qxe2x80x94R is xe2x80x94OCH2CO2R or xe2x80x94SCH2R1 where:
R is alkyl;
R1 is heteroaryl; and
R2 is aryl or heteroaryl; and
R6 is hydrogen, alkyl, halo, or alkoxy.
In a fourth aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fifth aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, propenylene, and the like.
xe2x80x9cAlkynylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a radical xe2x80x94OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, e.g., acetyl, benzoyl, thenoyl, and the like.
xe2x80x9cAcyloxyxe2x80x9d means a radical xe2x80x94OC(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, heterocyclyl or xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), e.g., acetoxy, and the like.
xe2x80x9cAcylaminoxe2x80x9d means a radical xe2x80x94NRC(O)Rxe2x80x2 where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, e.g., acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.
xe2x80x9cSulfonylaminoxe2x80x9d means a radical xe2x80x94NRSO2Rxe2x80x2 where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl or heteroaralkyl, e.g., methylsulfonylamino, benzylsulfonylamino, phenylsulfonylamino, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cMonosubstituted aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, alkenyl, heteroalkyl, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an amino protecting group, e.g., methylamino, (1-methylethyl)amino, phenylamino, and the like.
xe2x80x9cDisubstituted aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl, alkenyl, heteroalkyl, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, acyloxy, optionally substituted phenyl, heteroaryl, heteroaralkyl, xe2x80x94COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl or heteroalkyl), xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl), xe2x80x94NRC(O)R (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl), xe2x80x94COOR, -(alkenylene)-COOR, -(alkylene)-COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 and -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The aromatic radical is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, hydroxylamino, heteroalkyl, halo, nitro, cyano, heterocyclylalkyl, optionally substituted phenyl, xe2x80x94COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl), xe2x80x94NRRxe2x80x2 [where R and Rxe2x80x2 are independently of each other hydrogen, alkyl, cycloalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroalkyl, heterocyclylalkyl, -(alkylene)-COxe2x80x94Z (where Z is amino, alkylamino, or dialkylamino) or optionally substituted phenyl], xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroalkyl, heterocyclylalkyl or optionally substituted phenyl), xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRaC(O)Rb [where Ra or alkyl and Rb is hydrogen, alkyl, -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, optionally substituted heteroaryl ring or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl or cycloalkylalkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen, alkyl cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl), xe2x80x94COOR, -(alkenylene)-COOR, -(alkylene)-COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 and -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl, imidazolyl and derivatives thereof.
xe2x80x9cOptionally substituted heteroarylxe2x80x9d means a pyridyl, pyrimidinyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl or imidazolyl ring which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl, alkenyl, alkynyl or cycloalkyl radical as defined above, carrying one or two substituents selected from xe2x80x94NRaRb, xe2x80x94ORc, xe2x80x94S(O)nRd or xe2x80x94SO3xe2x88x92X+wherein n is an integer from 0 to 2, X+ is an alkali metal, Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxy, amino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclylalkyl, optionally substituted heteroaralkyl xe2x80x94SO2R (where R is alkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl) or -(alkylene)-COOR (where R is hydrogen or alkyl), Rb is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or optionally substituted heteroaralkyl, Rc is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, xe2x80x94COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl) or -(alkylene)-COOR (where R is hydrogen or alkyl) and Rd is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl). Representative examples include, but are not limited to, 2-methoxyethyl, phenoxymethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-hydroxyethoxy, 2-dimethylaminoethoxy, and the like.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cHeterocyclylxe2x80x9d means a cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycle ring may be optionally substituted independently with one or two substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, imidazole, halo, cyano, acyl, acylamino, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, imidazole or optionally substituted phenylalkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl or cycloalkylalkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen, alkyl, alkenyl, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), an amino protecting group, xe2x80x94COOR, -(alkylene)-COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 or -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl). More specifically the term heterocycle includes, but is not limited to, tetrahydropyranyl, pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, azepine, and derivatives thereof.
xe2x80x9cOptionally substituted heterocyclylxe2x80x9d means a tetrahydropyranyl, pyrrolidino, piperidino, piperazino, homopiperazino or morpholino ring which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl radical as defined above, carrying one or more, preferably one, two or three hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
xe2x80x9cAminoalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two amino groups, e,g., 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 1-(aminomethyl)-2-methylpropyl, and the like.
xe2x80x9cAlkylaminoalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two xe2x80x94NHR groups where R is an alkyl group as defined above. Representative examples include, but are not limited to, 2-methylaminoethyl, 3-ethylaminopropyl, 1-(methylaminomethyl)-2-methylpropyl, and the like.
xe2x80x9cDialkylaminoalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two xe2x80x94NRR groups where R is an alkyl group as defined above. Representative examples include, but are not limited to, 2-dimethylaminoethyl, 2-dimethylaminopropyl, 1-(dimethylamino-methyl)-2-methylpropyl, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two alkoxy group as defined above, e.g., 2-methoxyethyl, 2-methoxypropyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclyl group as defined above e.g., 2-(morpholin-4-yl)ethyl, 3-(piperidin-1-yl)-2-methylpropyl, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9caryl group optionally mono- or di-substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzene-sulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The nomenclature used in this application is generally based on the IUPAC recommendations, for example:
(i) a compound of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and 
is a group of formula (S) is numbered and named as follows: 
where Q is xe2x80x94NHxe2x80x94, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.
(ii) a compound of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and 
is a group of formula (T) is numbered and named as follows: 
where Q is xe2x80x94NH, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridine.
(iii) a compound of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and 
is a group of formula (U) is named and numbered as follows: 
where Q is xe2x80x94NHxe2x80x94, R1 is 4-pyridyl, R2 is phenyl and R3 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazine.
(iv) a compound of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and 
is a group of formula (V) is named and numbered as follows: 
where Q is xe2x80x94NHxe2x80x94, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine.
(v) a compound of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and 
is a group of formula (W) is named and numbered as follows: 
where Q is xe2x80x94NHxe2x80x94, R1 is 4-pyridyl, R2 is phenyl and R6 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.
(vi) a compound of Formula (I) where B is nitrogen, Q is xe2x80x94CHxe2x80x94, and 
is a group of formula (S) is named and numbered as follows: 
where R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 1-phenyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine.
(vi) a compound of Formula (I) where B is nitrogen, Q is xe2x80x94CHxe2x80x94, and 
is a group of formula (T) is named and numbered as follows: 
where R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 1-phenyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine.
(vii) a compound of Formula (I) where B is nitrogen, Q is xe2x80x94CHxe2x80x94, and 
is a group of formula (U) is named and numbered as follows: 
where R1 is 4-pyridyl, R2 is phenyl and R6 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-7H-pyrrolo[2,3-c]pyridazine.
(viii) a compound of Formula (I) where B is nitrogen, Q is xe2x80x94CHxe2x80x94, and 
is a group of formula (V) is named and numbered as follows: 
where Q is xe2x80x94NHxe2x80x94, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine.
Representative compounds of this invention are as follows:
I. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, R3 is hydrogen, 
is a group of formula (S), and the other groups are as defined below are:
II. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (S), and the other groups are as defined below are:
III. Compounds of Formula (I) where B is carbon, Q is xe2x80x94Oxe2x80x94, R3 and R6 are hydrogen, 
is a group of formula (S), and the other groups are defined below are:
IV. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, R3 and R6 are hydrogen, 
is a group of formula (T), and the other groups are as defined below is:
V. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, R6 is hydrogen, 
is a group of formula (W), and the other groups are as defined below is:
VI. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NR4xe2x80x94, R6 is hydrogen, 
is a group of formula (W), and the other groups are as defined below is:
VII. Compounds of Formula (I) where B is nitrogen, Q is xe2x80x94CHxe2x80x94, R6 is hydrogen, 
is a group of formula (S), and the other groups are as defined below are:
VIII. Compounds of Formula (I) where B is carbon, Q is xe2x80x94NHxe2x80x94, R3 and R6 are hydrogen, 
is a group of formula (V), and the other groups are as defined below are:
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred. For example,
A preferred group of compounds is that wherein is between B and xe2x80x94CR1xe2x80x94.
Within this group, more preferred groups are as follows:
I. One more preferred group of compounds is that wherein:
Q is xe2x80x94NR4xe2x80x94; and 
is a group represented by formula (S).
Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein:
(A) R2 is aryl;
R3 is at the 7-position and is hydrogen, alkyl, halo or heteroalkyl, more preferably hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl, most preferably hydrogen; and
R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.
Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein:
R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), xe2x80x94NaC(O)Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94OR (where R is alkyl or heteroalkyl), more preferably R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy, most preferably 2-acetylamino-4-pyridyl or 2-(2-hydroxyethylamino)-4-pyridyl; and
R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.
Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein:
R4 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, -(alkylene)-Z or -(alkyl)-CO-(alkylene)-Z wherein:
Z is xe2x80x94COOR7 where R7 is alkyl;
xe2x80x94CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or -(alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle; or
xe2x80x94C(xe2x95x90NR10)(NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl, or R10 and R11 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3 and R12 is hydrogen or alkyl; preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl.
(B) Another even more preferred group of compounds is that wherein:
R1 is a heteroaryl ring substituted with xe2x80x94NRRxe2x80x2 (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and Rxe2x80x2 is heterocyclylalkyl or heteroalkyl), preferably a 4-pyridyl or 4-pyrimidinyl ring substituted at the 2-position with xe2x80x94NRRxe2x80x2 (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and Rxe2x80x2 is heterocyclylalkyl or heteroalkyl), more preferably 2-hydroxyethylamino-4-pyridyl, 2-dimethylaminoethylamino-4-pyridyl, or 2-methylaminoethylamino-4-pyridyl; and
R2 is aryl.
Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein:
R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl;
R3 is at the 7-position and is hydrogen, alkyl, halo or heteroalkyl, more preferably hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl, most preferably hydrogen; and
R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.
Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein:
R4 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:
Z is xe2x80x94COOR7 where R7 is alkyl;
xe2x80x94CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or -(alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle; or
xe2x80x94C(xe2x95x90NR10)(NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl, or R10 and R11 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3; preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl) ethyl, 3-(piperazin-1-yl)propyl, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl.
II. A second more preferred group of compounds is that wherein:
Q is xe2x80x94NR4xe2x80x94; and 
is a group represented by formula (W).
Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein:
(A) R6 is at the 6-position and is selected from hydrogen, alkyl, alkoxy, halo, xe2x80x94NRC(O)Rxe2x80x3 [where R is hydrogen, alkyl or hydroxyalkyl and Rxe2x80x3 is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], preferably hydrogen, methyl, methoxy, fluoro, chloro, amino, 2-hydroxyethylamino, or acetylamino, most preferably hydrogen.
Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein:
R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), xe2x80x94NRaC(O)Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94OR (where R is alkyl or heteroalkyl), more preferably R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and
R2 is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.
Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein:
R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:
Z is xe2x80x94COOR7 where R7 is alkyl;
xe2x80x94CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or -(alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle; or
xe2x80x94C(xe2x95x90NR10)(NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl, or R10 and R11 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3; preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl) ethyl, 3-(piperazin-1-yl)propyl, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl.
Another even more preferred group of compounds is that wherein:
(B) R1 is a heteroaryl ring substituted with xe2x80x94NRRxe2x80x2 (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and R is heterocyclylalkyl or heteroalkyl), preferably a 4-pyridyl or 4-pyrimidinyl ring substituted at the 2-position with xe2x80x94NRRxe2x80x2 (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and Rxe2x80x2 is heterocyclylalkyl or heteroalkvl), preferably 2-hydroxyethylamino-4-pyridyl, 2-dimethylaminoethylamino-4-pyridyl, or 2-methylaminoethylamino-4-pyridyl; and
R2 is aryl.
Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein:
R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein:
Z is xe2x80x94COOR7 where R7 is alkyl;
xe2x80x94CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or -(alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle; or
xe2x80x94C(xe2x95x90NR10)(NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl, or R10 and R11 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3; preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl) ethyl, 3-(piperazin-1-yl)propyl, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl; and
R6 is at the 6-position of ring (W) and is selected from hydrogen, alkyl, alkoxy, halo, xe2x80x94NRC(O)Rxe2x80x3 [where R is hydrogen, alkyl or hydroxyalkyl and Rxe2x80x3 is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], preferably hydrogen, methyl, methoxy, fluoro, chloro, amino or acetylamino, most preferably hydrogen.
Within these preferred and more preferred groups and particularly preferred groups, an even more preferred group of compounds is that wherein:
R2 is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.
III. A third more preferred group of compounds is that wherein:
Q is xe2x80x94Oxe2x80x94; and 
is a group represented by formula (S).
Within these preferred and more preferred group of compounds, an even more preferred group of compounds is that wherein:
R3 is at the 7-position and is hydrogen, alkyl, cycloalkyl, heteroalkyl, halo, heterocyclylalkyl, xe2x80x94OR19 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Zxe2x80x3 or -(alkylene)-CO-(alkylene)-Zxe2x80x3 wherein:
Zxe2x80x3 is cyano;
xe2x80x94COOR24 where R24 is hydrogen or alkyl;
xe2x80x94CONR25R26 where R25 and R26 independently represent hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycle;
xe2x80x94C(xe2x95x90NR27)(NR28R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3 and R29 is hydrogen or
xe2x80x94COR30 where R30 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxy-propoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylamino-propoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)propoxy, 2-(piperidin-1-yl)ethoxy, 3-(piperidin-1-yl)propoxy, 2-(piperazin-1-yl)ethoxy or 3-(piperazin-1-yl)propoxy, more preferably hydrogen, hydroxy, methoxy, 2-(morpholin-4-yl)ethyl, 2-(morpholin-4-yl)ethoxy or 2-(piperidin-1-yl)ethyl; and
R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.
Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein:
R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), xe2x80x94NRaC(O)Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94OR (where R is alkyl or heteroalkyl), more preferably R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and
R2 is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR where R is alkyl, more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.
IV. A fourth more preferred group of compounds is that wherein:
Q is xe2x80x94Oxe2x80x94; and 
is a group represented by formula (W).
Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein:
R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.
Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein:
R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), xe2x80x94NRaC(O)Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)], xe2x80x94NRSO2Rxe2x80x3 [where R is hydrogen or alkyl and Rxe2x80x3 is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)nRxe2x80x2 (where n is 0 to 2 and Rxe2x80x2 is alkyl)] or xe2x80x94OR (where R is alkyl or heteroalkyl), more preferably R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and
R2 is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or xe2x80x94OR where R is alkyl, more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.
Exemplary particularly preferred compounds are:
3-(4-Fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.
3-(4-Fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.
3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.
3-(4-Fluorophenyl)-2-[2-(2-hydroxyethylamino)pyridin-4-yl]-1H-pyrrolo[3,2-b]pyridine.
3-(4-Fluorophenyl)-1-[2-(piperidin-1-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]-pyridine.
3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1-[2-(morpholin-4-yl)ethoxy]-1H-pyrrolo[3,2-b]-pyridine.
3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrolo[3,2-b]-pyridine.
3-(4-Fluorophenyl)-1-[2-(piperidin-1-yl)ethyl]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine.
7-(4-Fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine.
6-(2-Acetylaminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Lancaster (Windham, N.H., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Schemes A-M describe methods to synthesize compounds of Formula (I).
Compounds of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (S) or (T) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Reaction of an ester of formula 1 with an acetonitrile derivative of formula 2 in the presence of a suitable base such as sodium ethoxide or potassium t-butoxide, each in its respective alcohol as solvent gives a xcex2-keto-acetonitrile intermediate of formula 3 ((see., Ivan Lantos, I. et al. J. Org. Chem. 53, 4223-4227 (1988)). Alternatively, the reaction can be carried out in the presence of lithium diisopropylamide or lithium hexamethyldisilazane in tetrahydrofuran.
In general, compounds of formula 1 are commercially available or they can be prepared by methods well known in the art. For example, methylisonicotinate is commercially available. Others can be prepared from suitable starting materials such as 2-chloropyridine-4-carboxylic acid, 3- or 4-quinolinecarboxylic acid, 2-pyrazinecarboxylic acid, 4-methyl-5-pyrimidine-carboxylic acid, 4-pyrimidinecarboxylic acid, 2-pyrazinecarboxylic acid under standard esterification reaction conditions.
Compounds of formula 2 such as 2-phenylacetonitrile, 4-fluorophenylacetonitrile, pyridylacetonitrile, and the like are commercially available.
Hydrolysis and decarboxylation of the cyano group in 3 in a suitable aqueous acid such as hydrobromic acid provides a ketone of formula 4. Alternatively, a compound of formula 4 can be prepared directly, by reacting the sodium salt of an acid of formula R1COOxe2x88x92Na+ with a Grignard reagent of formula R2CH2MgX (where X is halo).
Condensation of 4 with a 3-aminopyridine of formula 5 or a 4-aminopyridine of formula 6 where X is a halo group (e.g., chloro, bromo or iodo) gives an enamine of formula 7 or 8 respectively. The condensation reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid in an aromatic hydrocarbon as a solvent e.g., toluene or xylene.
Compounds of formula 5 are either commercially available or they can be prepared by methods well known in the art. For example, 3-amino-2-chloropyridine is commercially available. 3-amino-2-chloro-6-bromopyridine and 3-amino-2-bromo-6-methoxypyridine can be prepared by following the procedure described in Proudfoot, J. R., et al., J. Med. Chem., 38(24), 4830, (1995). 3-amino-2,6-dichloro-4-methylpyridine can be prepared by following the procedure described in Grozinger, K. G., et al., J. Heterocycl. Chem., 32(1), 259, (1995). 3-amino-2,5-dichloropyridine can be prepared by first converting 5-chloro-3-nitro-2-pyridinone to 2,5-dichloro-3-nitropyridine as described in J. Heterocycl. Chem., 31(1), 73, (1994)) followed by reduction of the nitro group as described in Berrie et al., J. Chem. Soc., 2042 (1952).
Compounds of formula 6 such as 4-amino-3-chloropyridine and 4-amino-3-chloro-6-methylpyridine can be prepared by following the procedures described in Sugasawa, T., et al. J. Am. Chem. Soc., 4842-4851 (1978) and Turner J. A., J. Org. Chem., 48, 3401-3408 (1983) respectively. 4-amino-3-fluoro-6-methoxypyridine can be prepared by following the procedure described in Nesnow, H. J. Heterocycl. Chem., 12, 941, (1975).
Cyclization of the enamine 7 or 8 provides the 1H-pyrrolo[3,2-b]pyridine or the 1H-pyrrolo[3,2-c]pyridine of Formula (I), respectively. The cyclization reaction is carried out in the presence of a palladium (II) catalyst such as dichlorobis(triphenylphosphine)palladium (II) in the presence of a tertiary amine such as Dabco(trademark) and in an inert organic solvent such as dimethylformamide ((see., Chen, C. et al. J. Org. Chem., 62, 2676-2677 (1997) and Sakamoto, T. et al. Synthesis, 215 (1990)).
A compound of Formula (I) can be converted, if desired, to other compounds of Formula (I). For example,
(i) A 1H-pyrrolo-[3,2-b]pyridine or a 1H-pyrrolo-[3,2-c]pyridine of Formula (I), where R4 is hydrogen can be converted to its corresponding compound of Formula (I) where R4 is not hydrogen by reacting it with an alkylating agent R4Y where Y is a leaving group under alkylating conditions (such as halo, mesylate, tosylate and the like) or an acylating R4COL where L is leaving group under acylating reaction conditions such as halo (preferably chloro). The reaction is carried out in the presence of a strong base such as sodium hydride and in an aprotic organic solvent such as tetrahydrofuran, dimethylformamide, and the like.
(ii) A 1H-pyrrolo[3,2-b]pyridine or a 1H-pyrrolo-[3,2-c]pyridine of Formula (I) can be substituted at the 7-position (R3=7-position) using an ortho lithiation protocol. Thus, protection of the N1 nitrogen with an ortho directing protecting group such as trimethylsilylethoxymethyl (SEM), tert-butoxycarbonyl or N-tert-butyl carbamoyl, followed by lithiation with a strong base such as lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, n-butyllithium or tert-butyllithium in tetrahydrofuran or diethylether would lithiate the 7-position of the pyrrolo[3,2-b]pyridine/pyrrolo-[3,2-c]pyridine ring. Treatment of the 7-lithio species with an electrophile such as alkyl disulfide, iodine, dimethylformamide, carbon dioxide will give a corresponding pyrrolo[3,2-b]pyridine/pyrrolo-[3,2-c]pyridine of Formula (I) substituted at the 7-position with an iodo, formyl or carboxy group respectively ((see Gharpure, M.; et al. Synthesis, 12, 1079-82 (1991)).
Scheme B describes an alternative method to synthesize a compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (S) or (T) and other groups are as defined in the Summary of the Invention. 
Condensation of a compound of formula 9 with a 3-aminopyridine of formula 5 or 4-aminopyridine of formula 6 where X is a halo group (e.g., chloro, bromo or iodo) gives an enamine of formula 10 or 11 which is then cyclized to the 1H-pyrrolo[3,2-b]pyridine 12 or 1H-pyrrolo[3,2-c]pyridine 13 respectively, by proceeding as described in Scheme A above. The condensation reaction is carried out in the presence of a suitable base such as sodium hydride and in an aprotic solvent e.g., tetrahydrofuran or dimethylformamide.
Bromination of 12 or 13 with bromine in dimethylformamide gives the corresponding 3-bromo derivative which upon treatment with boronic acid of formula R2B(OH)2 (where R2 is as defined in the Summary of the Invention) under Suzuki coupling reaction conditions ((see., Miyaura, N. Chem. Commun., 866, (1979)) gives 1H-pyrrolo[3,2-b]pyridine or 1H-pyrrolo[3,2-c]pyridine of Formula (I) respectively.
A 1H-pyrrolo[3,2-b]pyridine or 1H-pyrrolo[3,2-c]pyridine of Formula (I) where R3, R4 and R6 are hydrogen can be converted to the corresponding 1H-pyrrolo[3,2-b]pyridine or 1H-pyrrolo[3,2-c]pyridine of Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above.
Scheme B describes an alternative method to synthesize a compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (T) and other groups are as defined in the Summary of the Invention. 
Reaction of a 4-aminopyridine of formula 14 where PG is an ortho-directing amino protecting group such as tert-butoxycarbonyl, pivaloyl or benzoyl, preferably pivaloyl, with a compound of formula 15, where L is a leaving group under acylating conditions [e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino, halo (preferably chloro), or preferably N,O-dimethylhydroxylamino] gives a 3-acyl-4-aminopyridine derivative of formula 16. The reaction is carried out in the presence of a strong base such as n-butyllithium in an aprotic polar organic solvents such as diethyl ether, tetrahydrofuran, and the like ((see., Sugasawa, T. et al. J. Am. Chem. Soc. 4842-4851 (1978)). 4-Aminopyridine is commercially available.
Deprotection of the amino group, followed by treatment of the resulting 4-aminopyridine 17 with an acyl halide of formula 18 in the presence of a non-nucleophilic base (such as triethylamine, pyridine and the like) gives a 4-amido-3-acylpyridine of formula 19. The deprotection is carried out under acidic hydrolysis reaction conditions. Suitable acids are inorganic acids such as hydrochloric acid.
Compounds of formula 18 where X is chloro can be prepared from suitable starting materials such as 2-chloropyridine-4-carboxylic acid, 3- or 4-quinolinecarboxylic acid, 2-pyrazinecarboxylic acid, 4-methyl-5-pyrimidinecarboxylic acid, 4-pyrimidinecarboxylic acid, 2-pyrazinecarboxylic acid by treatment with a chlorinating agent such as thionyl chloride, oxalyl chloride, and the like.
The 4-amido-3-acylpyridine 19 is converted to the 1H-pyrrolo[3,2-c]pyridine of Formula (I) (R4 is hydrogen) by following the procedure described in Furstner, A et al., J. Org. Chem., 59, 5215-5229, (1994).
A compound of Formula (I) where R4 is hydrogen can be converted to other compounds of Formula (I) where R4is not hydrogen as described in Scheme A above.
Compounds of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NOR5xe2x80x94, 
is a group of formula (S) or (T) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Reaction of a ketone of formula 4 with a 2-chloro-3-nitropyridine 20 or a 3-chloro-4-nitropyridine 21 under nucleophilic substitution reaction conditions gives an xcex1-(3-nitro-2-pyridyl)ketone of formula 22 or xcex1-(4-nitro-3-pyridyl)ketone of formula 23 respectively. The reaction is carried out in the presence of a strong non-nucleophilic base such as sodium hydride in an aprotic organic solvent such as dimethylformamide, and the like.
Compounds of formula 20 and 21 are either commercially available or they can be prepared by methods known in the art. For example, 2-chloro-3-nitropyridine, 3-chloro-4-nitropyridine, 2-chloro-4-methyl-3-nitropyridine, 2-chloro-6-methoxy-3-nitropyridine are commercially available. Compounds such as 2,5-dichloro-3-nitropyridine, 2-chloro-5,6-dimethyl-3-nitropyridine and 3-fluoro-4-nitro-2,6-dimethylpyridine can be prepared by the procedures described in Berrie et al., J. Chem. Soc., 2042, (1952), Wai, J. S., et al., J. Med. Chem., 36(2), 249, (1993), and Markley, E., J. Med. Chem., 16, 297, (1973), respectively
Conversion of 22 or 23 to the corresponding triflate derivatives 24 or 25, followed by nitro group reduction and concomitant ring cyclization gives the 1-hydroxy-1H-pyrrolo[3,2-b]pyridine or 1-hydroxy-1H-pyrrolo[3,2-c]pyridine (I) (R5=H), respectively. The triflate reaction is carried out by reaction 22 or 23 with triflic anhydride in the presence of a non-nucleophilic base such as triethylamine, pyridine, preferably pyridine. Suitable solvents are halogenated hydrocarbons such as dichloromethane, chloroform, and the like. The reductive cyclization reaction is carried out using tin (II) chloride dihydrate or titanium (III) chloride in solvents such as ethanol or ethyl acetate or it can be carried out under standard hydrogenolysis reaction conditions.
Alternatively, the 1-hydroxy-1H-pyrrolo[3,2-b]pyridine and 1-hydroxy-1H-pyrrolo[3,2-c]pyridine (I) can be prepared directly from 22 and 23 respectively, under the same ring cyclization reaction conditions without proceeding through the triflate intermediate.
A compound of Formula (I) where R5 is hydrogen can be converted its corresponding compounds of Formula (I) where R5 is other than hydrogen by reacting it with an alkylating agent R5Y, as described in Scheme A above.
Compounds of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94Oxe2x80x94, 
is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Protection of the hydroxy group in an ethyl 3-hydroxy-2-picolinate of formula 26 with a suitable protecting group (such as tert-butyldimethylsilyl, and the like) followed by treatment with an organometallic reagent such as an organolithium or Grignard reagent of formula 28 under nucleophilic substitution reaction conditions gives a 2-ketopyridine of formula 29. The reaction with the organometallic reagent is carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran, preferably diethyl ether. Ethyl 3-hydroxy-2-picolinate is prepared from commercially available 3-hydroxypicolinic acid by methods well known in the art.
Removal of the O-protecting group in 29 gives a 2-keto-3-hydroxypyridine of formula 30. The reaction conditions used for the deprotection depend on the nature of the protecting group. For example, if tert-butyldimethylsilyl is used then it is removed with tetrabutylammonium fluoride in an ethereal solvent such as tetrahydrofuran. For other suitable O-protecting groups see T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Wiley, New York (1991) and J. F. McOmie, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d Plenum Press, London (1973).
Reaction of 30 with ethyl bromoacetate in the presence of a non-nucleophilic base such as sodium hydride in a suitable organic solvent such as tetrahydrofuran gives a compound of formula 31. Treatment of 31 with base such as sodium ethoxide in ethanol, followed by thermolysis of the resulting 2-carboxyfuro[3,2-b]pyridine of formula 32 gives furo[3,2-b]pyridine of formula 33 ((see., Shiotani, S., and Moriata, H. J. Heterocyclic Chem., 23, 665 (1986))
o-Lithiation of 33 with a base such as lithium diisopropylamide or n-butyllithium, followed by treatment with an organotin reagent such as tributyltin chloride gives 34. Coupling of 34 with an organic halide of formula R1X (where X is chloro, bromo or iodo) then provides furo[3,2-b]pyridine of Formula (I). The reaction is carried out in the presence of a Pd(II) catalyst such as dichlorobis(triphenylphosphine)palladium (II) in inert organic solvent such as dimethylformamide or xylenes.
Substituting ethyl 3-hydroxy-2-picolinate 26 with ethyl 4-hydroxynicotinate ((see., Bojarska-Dahlig, Nantka-Namirski, Rocz. Chem., 29, (1955)) and proceeding as described in Scheme E above, gives furo[3,2-c]pyridine of Formula (I).
A compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94Sxe2x80x94, 
is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Reaction of a 3-fluoropyridine of formula 35 with a compound of formula 15 where L is a leaving group under acylating conditions [e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino, halo (preferably chloro), or preferably N,O-dimethylhydroxylamino] gives a 2-acyl-3-fluoropyridine of formula 36. The reaction is carried out in the presence of a Lewis acid such as boron trifluoride and a strong base such as lithium diisopropylamide and in an aprotic polar organic solvents such as diethyl ether, tetrahydrofuran, and the like ((see., Kessar, S. V. et al. J. Chem. Soc. Chem. Commun. 570 (1991) and Vedejs, E. and Chen, X. J. Am. Chem. Soc. 118, 1809-1810 (1996)).
Nucleophilic substitution of the fluoro group in 36 by a thiol reagent of formula 37 gives a compound of formula 38. The reaction is carried out in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran. A thiol reagent such as (4-pyridyl)methylthiol can be prepared by the procedure described in Barnes, J. H., J. Med. Chem., 23(3), 211, (1988).
Cyclization of 38 to thieno[3,2-b]pyridine of Formula (I) is achieved upon heating 38 in an alcoholic solvent such as ethanol in the presence of a base such as sodium ethoxide.
Substituting 3-fluoropyridine 35 with 4-fluoropyridine and following the procedure in Marsais, F., et al., J. Heterocycl. Chem., 25(1), 81, (1988) gives 3-acyl-4-fluoropyridine which can then be converted to thieno[3,2-c]pyridine of Formula (I) by proceeding as described in Scheme F above.
A compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (U) and other groups are as defined in the Summary of the Invention can be prepared as described below. 
Condensation of a ketone of formula 4 with a 4-aminopyridazine of formula 39 where X is a halo group (e.g., chloro, bromo or iodo) gives an enamine of formula 40. The condensation reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid or a Lewis acid such as aluminum chloride in an aromatic hydrocarbon as a solvent e.g., toluene or xylene. Compound 40 is then converted to 5H-pyrrolo[3,2-c]pyridazine of Formula (I) by proceeding as described in Scheme A above.
Compounds of formula 39 can be prepared by methods well known in the art. For example, 4-amino-3-chloropyridazine is prepared from commercially available 4,5-dichloropyridaz-3-one by first converting it to 4-chloro-5-hydrazinopyridaz-3-one by treatment with hydrazine under the reaction conditions described in Yakugaku Zasshi, 85, 344 (1965).
Removal of the hydrazino group with copper sulfate or silver oxide in aqueous medium gives 4-chloropyridaz-3-one which is then converted to 4-amino-3-chloropyridazine by following the procedure described in Klinge, D. E., Recueil des travaus chimiques des Pays-Bas, 93(8), 236-239, (1974).
A compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (V) and other groups are as defined in the Summary of the Invention can be prepared as described below. 
Condensation of a compound of formula 4 with hydrazine gives a hydrazone of formula 41. The reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid in an alcoholic solvent such as ethanol. Reaction of 41 with a pyrimidine of formula 42 provides a compound of formula 43 which is then converted to 5H-pyrrolo[3,2-d]pyrimidine of Formula (I) by heating 43 in high boiling solvent such as diethylene glycol.
A 5H-pyrrolo-[3,2-d-]pyrimidine of Formula (I) where R3, R4 and R6 are hydrogen can be converted to the corresponding 5H-pyrrolo[3,2-d]pyrimidine of Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above.
A compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is xe2x80x94NR4xe2x80x94, 
is a group of formula (W) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Condensation of a ketone of formula 4 with a 2-hydrazinopyrazine of formula 45 in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid gives a hydrazone of formula 46 ((see, J. C. S. Perkin I, 1361-1363, (1976)). Suitable solvents for the reaction are aromatic hydrocarbons such as toluene. Compounds of formula 4 are prepared as described in Scheme A. A compound of formula 45 where R6 is hydrogen is prepared by reacting chloropyrazine with hydrazine under conditions well known in the art ((see., Euro. J. Med. Chem., 24(3), 249-57 (1989) and J. Heterocyclic Chem., 11, 697-701, (1974)).
Conversion of 46 to a 5H-pyrrolo[2,3-b]pyrazine of Formula (I) where R4 is hydrogen is achieved by heating 46 in high boiling solvent such as diethylene glycol. For other suitable cyclization reaction conditions see R. J. Sundberg, xe2x80x9cIndoles,xe2x80x9d Academic Press, San Diego, Calif., 1996, p 55.
A compound of Formula (I) where R4 is hydrogen can be converted to other compounds of Formula (I) where R4 is not hydrogen as described in Scheme A above.
A compound of Formula (I) where is between B and xe2x80x94CR1xe2x80x94, Q is O or S, 
is a group of formula (W) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Reaction of a 3-pyrazinecarbonyl chloride of formula 47 (where X is a halo group such as chloro or bromo) with an organozinc reagent of formula R2ZnX under the reaction conditions such as those described in Negishi, E. et al., Tet. Lett., 24(47), 5181, (1983) gives a 2-ketopyrazine of formula 48. 2-chloro-3-pyrazinecarbonyl chlorides can be prepared by following the procedure described in Friary, R. J., Tetrahedron, 49(33), 7179 (1993).
Nucleophilic substitution of the halo group in 48 by ethyl glycolate or a thiol reagent of formula R1CH2SH gives a compound of formula 49 or 50 respectively. The reaction is carried out in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran. A compound of formula 49 or 50 is then converted to a furo[2,3-b]pyrazine or a thieno[2,3-b]pyrazine of Formula (I) respectively, by proceeding as described in Scheme E or F above.
Substituting 2-chloro-3-pyrazinecarbonyl chloride 47 with 5-chloro-4-pyrimidine-carbonyl chloride (see., U.S. Pat. No. 4,110,450) and following the procedures described above gives furo[3,2-d]pyrimidine or a thieno[3,2-d]pyrimidine of Formula (I), respectively.
A compound of Formula (I) where is between Q and xe2x80x94CR1xe2x80x94, B is nitrogen, 
is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Condensation of a 2-hydrazinopyridine of formula 51 with a ketone of formula 52 in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid gives a hydrazone of formula 53. Suitable solvents for the reaction are aromatic hydrocarbons such as toluene.
Compounds of formula 51 are either commercially available or they can be prepared by methods known in the art. For example, 2-hydrazinopyridine is commercially available. 3-chloro-2-hydrazinopyridine can be prepared by heating 2,3-chloropyridine with hydrazine under conditions well known in the art ((see., Euro. J. Med. Chem., 24(3), 249-57 (1989)). Compounds of formula 52 such as 2-, 3-, 4-acetylpyridine, 2-acetylpyrazine are commercially available.
Conversion of 53 to a 1H-pyrrolo[2,3-b]pyridine of formula 54 is achieved by heating 53 in high boiling solvent such as diethylene glycol. For other suitable cyclization reaction conditions see., R. J. Sundberg, xe2x80x9cIndoles,xe2x80x9d Academic Press, San Diego, Calif. , 1996, p 55.
Conversion of 54 to a compound of Formula (I) where R is hydrogen is achieved by reacting 54 with an aryl halide of formula R2X (where R2 is as defined in the Summary of the Invention and X is a halo group) under the reaction conditions such as those described in Smith III, W. J. and Sawyer, J. S., Tet. Lett., Vol. 37(3), 299-302 (1996) or Zhang, Lin-hua et al., Tet. Lett., Vol. 36(46), 8387-8390, (1995).
A compound of Formula (I) where R is hydrogen can be converted to the corresponding compound of Formula (I) where R is other than hydrogen by following the procedures described in R. J. Sundberg, xe2x80x9cIndoles,xe2x80x9d Academic Press, San Diego, Calif., 1996, p 105-118.
Substituting 2-hydrazinopyridine 51 with 4-hydrazinopyrimidine, 3-hydrazinopyridazine or 2-hydrazinopyrazine and following the procedure described above gives 7H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-c]pyridazine or 5H-pyrrolo[2,3-b]pyrazine respectively.
4-Hydrazinopyrimidine and 3-hydrazinopyridazine can be prepared as described in Barlin, G. B., et al., J. Chem. Soc., Perkin Trans. 1 (1972) and Pinza, M. et al., Farmaco, 49(11), 683-92 (1994) respectively.
An alternative route for preparing a compound of Formula (I) where is between Q and xe2x80x94CR1xe2x80x94, B is nitrogen, 
is a group of formula (S) and other groups are as defined in the Summary of the Invention is described below. 
Reaction of a 2-chloro-3-iodopyridine of formula 55 with an amine of formula 56 gives a 2-amino-3-iodopyridine of formula 57. The reaction is carried out in the presence of a non-nucleophilic base such as pyridine. 2-chloro-3-iodopyridine can be prepared by the procedures described in Guillier, F., et al, Tet. Lett., 35(35), 6489, (1994) and Rocca, P. et al., Tetrahedron, 49(1), 49, (1993). Compounds of formula 56 such as aniline, 4-fluoroaniline, 4-methylaniline are commercially available.
Coupling of 57 with an alkyne of formula 58 gives 3-alkynyl-2-aminopyridine of formula 59 which is then cyclized to 1H-pyrrolo[2,3-b]pyridine of formula (I). The alkynyl coupling reaction is carried under the reaction conditions such as those described in de Souza, P. T. Quim. Nova, 19(4), 377 (1996). The cyclization reaction is carried out in the presence of a palladium (II) catalyst and in an inert organic solvent such as acetonitrile or tetrahydrofuran ((see., Iritani, K. et al. Tet. Lett., 29(15), 1799 (1988)).
Compounds of formula 58 such as 2-ethynylpyridine, 4-ethynylpyridine can be prepared by the procedure described in Yashima, E. et al., Japan Chirality, 9(5/6), 593-600 (1997).
Compounds of Formula (I) where is between Q and xe2x80x94CR1xe2x80x94, B is nitrogen, 
is a group of formula (T) and other groups are as defined in the Summary of the Invention are prepared as described below. 
Reaction of a 4-methyl-3-nitropyridine of formula 60 with N,N-dimethylformamide diethyl acetal in N,N-dimethylformnamide gives a 4-(2-dimethylaminoethylene)-3-nitropyridine of formula 61. Treatment of 61 with an acyl halide of formula R1COX (where R1 is as defined in the Summary of the Invention and X is a halo group) gives a ketone of formula 62 which upon reduction either catalytically or with sodium hydrosulfite provides a 2-substituted pyrrolo[2,3-c]pyridine of formula 63. Conversion of 60 to 63 is carried out under the reaction conditions described in Garcia, E. E and Fryer, R. I., J. Heterocyclic Chem., 11, 219, (1974).
A compound of formula 63 is then converted to a compound of Formula (I) as described in Scheme K above.
Compounds of Formula (I) can also be prepared by modification of a group present on a corresponding compound of Formula (I) by known procedures. Some examples of such procedures are described below:
(i) A compound of Formula (I) where R6 is alkoxy can be prepared from a corresponding compound of Formula (I) where R6 is chloro or bromo by treating it with an alkoxide under known reaction conditions. De-alkylation of an alkoxy substituent provides a corresponding compound of Formula (I) where R6 is hydroxy which can then be converted to a corresponding compound of Formula (I) where R6 is heteroalkyloxy or heterocyclylalkyloxy by treatment with the appropriate alkylating agent. Alternatively, the heteroalkyloxy can be put on by following literature procedures described in J. Org. Chem., 61, 7240, (1996) and Tetrahedron, 44, 91, (1988) respectively.
(ii) Compounds of Formula (I) where R6 is monosubstituted amino or disubstituted amino can be prepared by reacting the corresponding compound of Formula (I) where R6is chloro or bromo with a primary or secondary amine either in the presence or absence of a palladium catalyst as described in Wagaw, S; et al. J. Org. Chem. 61(21), 7240 (1996) and Wolfe, J. P.; et al. Tet. Lett. 38(36), 6367 (1997).
(iii) Compounds of Formula (I) where R6 is cyano can be prepared by reacting the corresponding compound of Formula (I) where R6 is chloro or bromo with copper cyanide in N,N-dimethylformamide or dimethyl sulfoxide as described in Heterocycles, 41 (12), 2799, (1995). Alternatively, it can be done with potassium cyanide in the presence of nickel or zinc catalyst as described in Bull. Chem. Soc. Jpn., 66(9), 2776, (1993).
(iv) Compounds of Formula (I) where R6 is alkyl can be prepared by reacting the corresponding compound of Formula (I) where R6 is chloro or bromo with alkyllithium or an alkyltin reagent in the presence of a palladium catalyst.
It will be recognized by one skilled in the art that these transformation are not limited to the R6 position but may be carried out at other positions in the compound of Formula (I).
Preparation of 7-(4-fluorophenyl)-6-[2-(3-hydroxypropylamino)pyridin-4-yl]-5H-pyrrolo[2,3-b]pyrazine from 7-(4-fluorophenyl)-6-[2-bromopyridin-4-yl]-5H-pyrrolo[2,3-b]pyrazine is described in Example 12.
The compounds of Formula (I) are p38 MAP kinase and JNK inhibitors and therefore compounds of Formula (I) and compositions containing them are useful in the treatment of diseases such as rheumatoid arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, toxic shock syndrome, endotoxic shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer""s and Parkinson""s diseases.
The ability of the compounds of Formula (I) to inhibit p38 MAP kinase was demonstrated by the in vitro assay described in Example 20. The ability of the compounds of Formula (I) to inhibit the release of TNF-xcex1 was demonstrated by the in vitro and the in vivo assays described in detail in Examples 21 and 22, respectively.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 0.5-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences; edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 19.